Breast Cancer Relapse Research Articles

Enhanced breast Cancer Relapse Prediction Based on Ensemble Learning Approaches

Predicting progression and deciding on the best follow-up techniques for breast cancer patients is difficult because the illness is diverse and characterized by varying relapse risks. Due to its prevalence, breast cancer has become the top cause of mortality among women worldwide, making diagnosis and prognosis particularly challenging areas of medical study. In addition, the fear of a cancer relapse is a major factor influencing cancer patients' quality of life. The study aims to help doctors determine the likelihood of a breast cancer relapse by applying ensemble learning techniques. In this research, artificial neural networks (ANN) and deep neural networks (DNN) ensembled with Weighted averaging, minority, and majority voting approaches have been investigated for performance enhancements on the breast cancer recurrence dataset sourced from the UCI-ML repository. The empirical analysis shows that this ensemble learning-enabled proposed novel approach shows improved accuracy, precision, sensitivity, specificity, and F1-score of 96.21%, 96.59%, 98.84%, 84.62%, and 97.41%, respectively. The findings of this study can aid doctors in making more informed treatment decisions, thereby improving patient outcomes.

Predictive Significance of Systemic Immune-Inflammation Index in Patients with Breast Cancer: A Retrospective Cohort Study.

Peripheral blood inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have become research hotspots in the diagnosis, treatment, and prognosis prediction of breast cancer, whereas existing research findings remain controversial. Data pertaining to 1808 breast cancer patients were collected retrospectively to analyze the predictive value of NLR/PLR/SII for breast cancer clinicopathological characteristics, chemotherapy response, and relapse. 1489, 258, and 53 eligible breast cancer patients entered into the three analyses, respectively. Logistic regression analyses were used to assess the correlation between these indices and poor response to chemotherapy. A predictive scoring model was established to predict chemotherapeutic responses based upon the odds ratio values of significant variables identified in logistic regression analyses. Higher pretherapeutic NLR/PLR/SII values were significantly correlated with higher tumor stage, triple-negative breast cancer, premenopausal status, and younger age. Logistic regression analyses indicated that pretherapeutic high SII (as a continuous variable or with a cut-off value of 586.40) and HER2-negative status were independent predictors of poor response to neoadjuvant chemotherapy. A first-in-class SII-based predictive scoring model well distinguished patients who might not benefit from neoadjuvant chemotherapy, with an area under the curve of 0.751. In HR-positive cancers, SII was more strongly associated with clinicopathological features and chemotherapy response. In addition, a receiver operating characteristic curve analysis indicated that the specificity of follow-up SII in identifying cancer relapse was greater than 98.0% at a cut-off value of 900. As a predictor of breast cancer, especially in the HR-positive subtype, SII may eclipse NLR/PLR. SII-high patients are more likely to have a worse chemotherapy response and a higher risk of recurrence.

P16 The wood for the trees

P16 The wood for the trees

Genome-Wide Characterization of TAZ Binding Sites in Mammary Epithelial Cells.

The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast cancer (BLBC) patients. The oncogenic activity of TAZ involves the regulation of diverse signal transduction pathways that direct processes such as cell proliferation, migration, and resistance to apoptosis, albeit through poorly characterized gene expression programs. Here, using a tet-inducible system in mammary epithelial MCF10A cells, we have characterized the TAZ-regulated transcription program using RNA sequencing in a temporal and spatial manner. We further identified global TAZ binding sites at different TAZ activation time points by chromatin immunoprecipitation (ChIP) sequencing analysis. We found that the vast majority of TAZ was rapidly localized in enhancer regions at the early TAZ activation time point and then gradually spread to promoter regions. TAZ bound to enhancer regions following a switch in potential TEAD and FOSL2 transcription factor motifs. Furthermore, the ATAC sequencing analysis indicated that TAZ activation led to chromatin structural alterations. Together, our results have revealed the landscape of genome-wide TAZ binding sites and may lead to improvements in the current understanding of how TAZ regulates the gene expression program that contributes to the development of breast cancer.

Use of Circulating Tumor DNA (ctDNA) for Early Molecular Detection of Breast Cancer Relapse in Patients with Triple-Negative Breast Cancer (TNBC)

Use of Circulating Tumor DNA (ctDNA) for Early Molecular Detection of Breast Cancer Relapse in Patients with Triple-Negative Breast Cancer (TNBC)

Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer.

Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P = .005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P = .001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P = .042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

CYP2C19*17 association with higher plasma 4-hydroxy tamoxifen in Pakistani (estrogen-positive) breast cancer patients.

Breast cancer (BC) continues to be the most common cancer in the women worldwide. Since estrogen receptor (ER)-positive BC accounts for the majority of newly diagnosed cases, endocrine therapy is advised to utilize either tamoxifen (Tam) or aromatase inhibitors. The use of Tam as a monotherapy or in conjunction with an aromatase inhibitor following two or three years of endocrine therapy has long been recommended. When used adjuvantly, Tam medication reduces BC mortality and relapses, while it extends survival times in metastatic BC when used in conjunction with other treatments. Unfortunately, the efficiency of Tam varies considerably. This study was conducted to explore the influence of genetic polymorphisms in CYP2C19 gene on Tam's pharmacogenetics and pharmacokinetics in estrogen-positive BC patients. Data from healthy, unrelated individuals (n = 410; control group) and ER-positive BC patients (n = 430) receiving 20 mg of Tam per day were recruited. Steady-state plasma concentrations of Tam and its three metabolites were quantified using the high-performance liquid chromatography in the patients. The CYP2C19 polymorphisms were genotyped using an Amplification Refractory Mutation System-Polymerase Chain Reaction (ARMS-PCR) approach. More than 65% of healthy individuals were extensive metabolizers (*1/*1) for CYP2C19, whereas more than 70% of ER-positive BC patients were rapid and ultrarapid metabolizers (*1/17*, *17/17*). The polymorphism CYP2C19*17 is significantly associated with higher 4-hydroxytamoxifen (4-OH-Tam). Patients with the *17/*17 genotype exhibited 1- to 1.5-fold higher 4-OH-Tam, which was also high in patients with the *1/*2 and *2/*2 genotypes.

Aberrant activation of five embryonic stem cell-specific genes robustly predicts a high risk of relapse in breast cancers

BackgroundIn breast cancer, as in all cancers, genetic and epigenetic deregulations can result in out-of-context expressions of a set of normally silent tissue-specific genes. The activation of some of these genes in various cancers empowers tumours cells with new properties and drives enhanced proliferation and metastatic activity, leading to a poor survival prognosis.ResultsIn this work, we undertook an unprecedented systematic and unbiased analysis of out-of-context activations of a specific set of tissue-specific genes from testis, placenta and embryonic stem cells, not expressed in normal breast tissue as a source of novel prognostic biomarkers. To this end, we combined a strict machine learning framework of transcriptomic data analysis, and successfully created a new robust tool, validated in several independent datasets, which is able to identify patients with a high risk of relapse. This unbiased approach allowed us to identify a panel of five biomarkers, DNMT3B, EXO1, MCM10, CENPF and CENPE, that are robustly and significantly associated with disease-free survival prognosis in breast cancer. Based on these findings, we created a new Gene Expression Classifier (GEC) that stratifies patients. Additionally, thanks to the identified GEC, we were able to paint the specific molecular portraits of the particularly aggressive tumours, which show characteristics of male germ cells, with a particular metabolic gene signature, associated with an enrichment in pro-metastatic and pro-proliferation gene expression.ConclusionsThe GEC classifier is able to reliably identify patients with a high risk of relapse at early stages of the disease. We especially recommend to use the GEC tool for patients with the luminal-A molecular subtype of breast cancer, generally considered of a favourable disease-free survival prognosis, to detect the fraction of patients undergoing a high risk of relapse.

Minimal residual disease (MRD) detection in solid tumors using circulating tumor DNA: a systematic review.

Minimal residual disease (MRD) refers to a very small number of residual tumor cells in the body during or after treatment, representing the persistence of the tumor and the possibility of clinical progress. Circulating tumor DNA (ctDNA) is a DNA fragment actively secreted by tumor cells or released into the circulatory system during the process of apoptosis or necrosis of tumor cells, which emerging as a non-invasive biomarker to dynamically monitor the therapeutic effect and prediction of recurrence. The feasibility of ctDNA as MRD detection and the revolution in ctDNA-based liquid biopsies provides a potential method for cancer monitoring. In this review, we summarized the main methods of ctDNA detection (PCR-based Sequencing and Next-Generation Sequencing) and their advantages and disadvantages. Additionally, we reviewed the significance of ctDNA analysis to guide the adjuvant therapy and predict the relapse of lung, breast and colon cancer et al. Finally, there are still many challenges of MRD detection, such as lack of standardization, false-negatives or false-positives results make misleading, and the requirement of validation using large independent cohorts to improve clinical outcomes.

Complex Analysis of Endothelial Markers as Potential Prognostic Indicators in Luminal Invasive Breast Carcinoma Patients: Outcomes of a Six-Year Observational Study.

(1) Background: Metastasis is a complex process in which the primary cancer cells spread to a distant organ or organs, creating a secondary tumor location, which in many patients leads to treatment failure and death. The aim of the present study was to assess the association of endothelial markers (i.e., sP-selectin, sE-selectin and von Willebrand factor) with the leptin-to-adiponectin ratio (LAR) and to perform an analysis of the predictive value on the survival of patients with luminal A and B invasive breast cancer (IBrC). (2) Methods: The trial included 70 treatment-naïve early-stage IBrC patients with a median age of 54.5 years and a median tumor diameter of 1.5 cm. The median duration of follow-up was 5.7 years, with a relapse rate of 15.71%. Specific immunoenzymatic kits were used to determine pre- and post-treatment concentrations of analyzed factors. (3) Results: Regardless of the treatment pattern, endothelial marker concentrations and the LAR increased after adjuvant treatment. The follow-up showed a significantly higher relapse rate in patients with IBrC who had higher pre-treatment sP-selectin and post-treatment LAR levels. According to receiver operating characteristic (ROC) analysis, a post-treatment LAR with a sensitivity of 88.9% and specificity of 57.9% discriminating cases with or without disease relapse. Additionally, a higher risk of breast cancer relapse was associated with a lower post-treatment sP-selectin concentration. (4) Conclusions: Our results showed mainly that pre-treatment sP-selectin levels and post-treatment LAR may have value as prognostic indicators and may contribute to predicting the future outcomes in patients with early-stage IBrC.

Contribución de la medicina nuclear en la cirugía de precisión en el cáncer de mama

Nuclear medicine has significantly contributed to precision surgery in breast cancer in the past decades. Radioguided surgery (RGS) has enabled sentinel node (SN) biopsy in assessing regional nodal involvement modifying the management of patients with early breast cancer. For the axilla the SN procedure has resulted in fewer complications and better quality of life when compared with axillary lymph node dissection. Originally, SN biopsy principally concerned cT1-2 tumors without evidence of axillary lymph node metastases. However, in last years SN biopsy is also being offered to patients with large or multifocal tumors, ductal carcinoma in situ, ipsilateral breast cancer relapse, and to patients receiving neoadjuvant systemic treatment (NST) for breast sparing surgery. Parallel to this evolution various scientific associations are trying to homogenise issues such as radiotracer choice, breast injection site, preoperative imaging standardisation and SN biopsy timing in relation to NST as well as management of non-axillary SN metastasis (e.g. internal mammary chain). Additionally, RGS is currently used to accomplish primary breast tumour excision either by intralesional radiocolloid injection or by radioactive iodine seed implantation which is also employed to target metastatic axillary lymph nodes. This latter procedure contributes to manage the node-positive axilla in combination with 18F-FDG PET/CT in an effort to tailor systemic and loco regional treatment.

MiR-662 is associated with metastatic relapse in early-stage breast cancer and promotes metastasis by stimulating cancer cell stemness.

Breast cancer (BC) metastasis, which often occurs in bone, contributes substantially to mortality.MicroRNAs play a fundamental role in BC metastasis, although microRNA-regulated mechanisms driving metastasis progression remain poorly understood. MiRome analysis in serum from BC patients was performed by TaqMan™ low-density array. MiR-662 was overexpressed following MIMIC-transfection or lentivirus transduction. Animal models were used to investigate the role of miR-662 in BC (bone) metastasis. The effect of miR-662-overexpressing BC cell conditioned medium on osteoclastogenesis was investigated. ALDEFLUOR assays were performed to study BC stemness. RNA-sequencing transcriptomic analysis of miR-662-overexpressing BC cells was performed to evaluate gene expression changes. High levels of hsa-miR-662 (miR-662) in serum from BC patients, at baseline (time of surgery), were associated with future recurrence in bone. At an early-stage of the metastatic disease, miR-662 could mask the presence of BC metastases in bone by inhibiting the differentiation of bone-resorbing osteoclasts. Nonetheless, metastatic miR-662-overexpressing BC cells then progressed as overt osteolytic metastases thanks to increased stem cell-like traits. MiR-662 is involved in BC metastasis progression, suggesting it may be used as a prognostic marker to identify BC patients at high risk of metastasis.

Inhibition of Autophagy and the Cytoprotective Role of Smac Mimetic against ROS-Induced Cancer: A Potential Therapeutic Strategy in Relapse and Chemoresistance Cases in Breast Cancer.

With more than a million deaths each year, breast cancer is the top cause of death in women. Around 70% of breast cancers are hormonally responsive. Although several therapeutic options exist, cancer resistance and recurrence render them inefficient and insufficient. The major key reason behind this is the failure in the regulation of the cell death mechanism. In addition, ROS was also found to play a major role in this problem. The therapeutic benefits of Smac mimetic compound (SMC) BV6 on MCF7 were examined in the current study. Treatment with BV6 reduces viability and induces apoptosis in MCF7 breast cancer cells. BV6 suppresses autophagy and has demonstrated a defensive role in cancer cells against oxidative stress caused by H2O2. Overall, the present investigation shows that SMC has therapeutic and cytoprotective potential against oxidative stress in cancer cells. These Smac mimetic compounds may be used as anti-cancer drugs as well as antioxidants alone or in conjunction with other commonly used antioxidants.

Nuclear medicine contribution to precision surgery in breast cancer

Nuclear medicine has significantly contributed to precision surgery in breast cancer in the past decades. Radioguided surgery (RGS) has enabled sentinel node (SN) biopsy in assessing regional nodal involvement modifying the management of patients with early breast cancer. For the axilla the SN procedure has resulted in fewer complications and better quality of life when compared with axillary lymph node dissection. Originally, SN biopsy principally concerned cT 1-2 tumours without evidence of axillary lymph node metastases. However, in last years SN biopsy is also being offered to patients with large or multifocal tumours, ductal carcinoma in situ, ipsilateral breast cancer relapse, and to patients receiving neoadjuvant systemic treatment (NST) for breast sparing surgery. Parallel to this evolution various scientific associations are trying to homogenise issues such as radiotracer choice, breast injection site, preoperative imaging standardisation and SN biopsy timing in relation to NST as well as management of non-axillary SN metastasis (e.g. internal mammary chain). Additionally, RGS is currently used to accomplish primary breast tumour excision either by intralesional radiocolloid injection or by radioactive iodine seed implantation which is also employed to target metastatic axillary lymph nodes. This latter procedure contributes to manage the node-positive axilla in combination with 18F-FDG PET/CT in an effort to tailor systemic and loco regional treatment.

Downregulation of circ-Foxo3 in breast cancer stem-like cells

ObjectiveCancer cells having stem cell characteristics are linked to metastasis and relapse in breast cancer. Circ-Foxo3, as a circular RNA, has been linked to the breast cancer lethal traits. This study’s objective was to assess circ-Foxo3 expression in breast cancer stem-like cells. After isolation from tumor mass, breast cancer cells were subjected to the reliable in vitro assay of spheroid formation to determine the presence cancer stem cells (CSCs). We used a quantitative real-time polymerase chain reaction to examine circ-Foxo3 expression in spheroids.ResultsCirc-Foxo3 expression was significantly downregulated in spheroid-forming tumor cells, according to our data. This study demonstrated that breast CSCs have downregulated circ-Foxo3 expression, which may allow these cells to evade apoptosis. A precise analysis of this circRNA’s role could be exploited to develop focused therapeutic approaches to fight breast CSCs.

MCP-1 expression in breast cancer and its association with distant relapse.

Distant relapse of breast cancer complicates management of the disease and accounts for 90% of breast cancer-related deaths. Monocyte chemoattractant protein-1 (MCP-1) has critical roles in breast cancer progression and is widely accepted as a pro-metastatic chemokine. This study explored MCP-1 expression in the primary tumour of 251 breast cancer patients. A simplified 'histoscore' was used to determine if each tumour had high or low expression of MCP-1. Patient breast cancers were retrospectively staged based on available patient data. p < 0.05 was used to determine significance and changes in hazard ratios between models were considered. Low MCP-1 expression in the primary tumour was associated with breast cancer-related death with distant relapse in ER- breast cancers (p < 0.01); however, this was likely a result of most low MCP-1-expressing ER- breast cancers being Stage III or Stage IV, with high MCP-1 expression in the primary tumour significantly correlated with Stage I breast cancers (p < 0.05). Expression of MCP-1 in the primary ER- tumours varied across Stage I, II, III and IV and we highlighted a switch in MCP-1 expression from high in Stage I ER- cancers to low in Stage IV ER- cancers. This study has emphasised a critical need for further investigation into MCP-1's role in breast cancer progression and improved characterisation of MCP-1 in breast cancers, particularly in light of the development of anti-MCP-1, anti-metastatic therapies.

Impact of implant surface type on breast cancer relapse after breast reconstruction: a propensity score-matched study.

Impact of implant surface type on breast cancer relapse after breast reconstruction: a propensity score-matched study.

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort

BackgroundEarly metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity. MethodsAll ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months). ResultsPatients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3–10.9) in patients with early relapse versus 17.1 months (95% CI 15.7–18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73–2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9–3.4) and 5.3 months (95% CI 5.1–5.8); (aHR: 1.66; [95% CI 1.50–1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS. ConclusionThese real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC.Database registration: clinicaltrials.gov Identifier NCT032753

Detection of circulating tumor DNA following neoadjuvant chemotherapy and surgery to anticipate early relapse in ER positive and HER2 negative breast cancer: Analysis from the PENELOPE-B trial.

502 Background: The PENELOPE-B phase III trial investigated the addition of one year of palbociclib to endocrine therapy (ET), in patients with hormone receptor positive HER2 negative breast cancer with residual invasive disease after neoadjuvant chemotherapy. Prior research has demonstrated that detection of circulating tumor DNA (ctDNA) in the adjuvant setting is associated with a high risk of disease relapse. We assessed the potential of ctDNA analysis to predict future clinical relapse for patients enrolled in the PENELOPE-B trial. Methods: Patients who were endocrine naïve at the time of study entry were selected for ctDNA analysis. Plasma samples were collected at baseline (after completion of neoadjuvant chemotherapy and surgery), prior to cycle 7 (approximately 6 months into ET +- palbociclib), end of treatment (EOT), and progressive disease. A tumor sample was subjected to exome sequencing, and up to 50 tumor somatic mutations were tracked in plasma using error-corrected sequencing combined with a proprietary algorithm for ctDNA detection (RaDaR assay). Detection of ctDNA was associated with invasive disease-free survival (iDFS) and distant metastasis-free survival using Cox proportional hazard models. Results: Of 1250 patients enrolled in PENELOPE-B, 129 were endocrine naïve at trial entry, and 78 had a baseline ctDNA sample analyzed. The ctDNA analysis group was representative of the overall endocrine naïve group, with median follow-up of 42.9 months. Seven patients had baseline ctDNA detected, with detection strongly associated with iDFS (HR 8.8, 95% CI 3.3-23.4, p &lt; 0.0001). Detection of ctDNA at cycle 7 (4 patients) was also strongly associated with iDFS (HR 25.5, 95% CI 6.5-99.6, p &lt; 0.0001). Of the 7 patients with baseline ctDNA detection, 2 had undetectable ctDNA at cycle 7 and remained progression free at 30 months, although one later relapsed; the 3 patients with detectable ctDNA at cycle 7 all relapsed within 25 months. Of the 12 patients with a distant relapse within 24 months, only 4 had ctDNA detected at baseline and 3 first at cycle 7/EOT. Of the 8 patients with distant relapse after 24 months, 2 had ctDNA detected at baseline and none first at cycle 7/EOT. Conclusions: Detection of ctDNA following neoadjuvant chemotherapy, and surgery, is associated with a very high risk of early relapse suggesting limited efficacy of adjuvant ET. Clinical imaging and studies of experimental therapy are warranted in this patient population. Testing ctDNA after recent neoadjuvant chemotherapy in luminal-A like breast cancer has relatively low ‘sensitivity’ for predicting future relapse, in particular for later relapses, in part suggesting that response to neoadjuvant chemotherapy may reduce ctDNA detection. Clinical trial information: NCT01864746 .

CtDNA mutational profiles in luminal breast cancer with early vs late distant relapse: Geicam/2014-03.

1060 Background: Patients with hormone receptor-positive early breast cancer (BC) can develop resistance to endocrine therapies (ET) and face a continuous risk of relapse, which can occur anywhere from a few months (m) to several decades after surgery. The causes of early vs late relapses are not well understood. Our research examines the presence of oncogenic drivers in circulating tumor DNA (ctDNA) at the time of relapse in patients with luminal BC who have either an early or late distant recurrence. Methods: We identified pts included in the GEICAM/2014-03 study (NCT02819882) with: 1) HR-positive BC, 2) metastatic relapse either &lt;36m (early relapse, [early-R]) or &gt;120m (late relapse, [late-R]) from diagnosis, and 3) ctDNA obtained before first line treatment for advanced disease. The AVENIO ctDNA assay was used for identifying genomic aberrations in 77 cancer-related genes. Results: Eighty-four pts, 36 in early-R and 48 in late-R groups, were selected. Median time to relapse was 24.97m in early-R vs 151.84m in late-R. Median time from last dose of adjuvant ET to relapse was 0.03m for early-R vs 74.06m for late-R. Median PFS to first line treatment was 7.62m in early-R and 35.15m in late-R. With a median follow-up of 32.08m, median OS after diagnosis of metastatic disease was 27.74m for early-R and not reached for late-R. ctDNA analysis detected at least 1 mutation (mut) in 71/84 (85%) pts (89% in early-R vs 81% in late-R). Early-R pts were enriched in mut in TP53 (44% vs 19%), ESR1 (11% vs 4%), MAPK_ERK pathway (14% vs 6%), and ERBB2 copy number alterations (CNA) (25% vs 2%). PI3K/AKT pathway alterations had similar frequency in both recurrence groups (38% vs 42%) and they were not associated with OS. Seven ESR1 mut were detected in 6 pts. In the early-R group there were 5 ESR1 mut (71% of total ESR1 mut), median mutant allele frequency (mMAF): 0.64%; while in the late-R, 2 ESR1 mut (29%), mMAF: 0.4%. ESR1 mut were associated with worse OS (median OS 48.48m vs 12.84m wild-type vs mutant; p=0.0025). There were 10 pts with E RBB2 CNA at metastatic relapse; 9 (25%) in the early-R and 1 pts (2%) in the late-R. Seven pts (70%) had HER2-positive. Pts with ctDNA ERBB2 CNA had worse OS (median OS 48.48m vs 20.52m wild-type vs mutant; p-adj=0.025). Conclusions: In luminal breast cancer (BC), early and late distant relapse differ at both the clinical and genomic levels. Early relapse is a highly aggressive form of the disease and is enriched in TP53 mutations and actionable genetic alterations, such as mutations in the ESR1 and CNA in ERBB2, as detected by ctDNA analysis at the time of metastatic relapse diagnosis. Clinical trial information: NCT02819882 . [Table: see text]